Challenges and solutions in clinical research during the COVID‐19 pandemic: A narrative review

Abstract Background and Aims The COVID‐19 pandemic has presented significant challenges to clinical research, necessitating the adoption of innovative and remote methods to conduct studies. This study aimed to investigate these challenges and propose solutions for conducting clinical research during the pandemic. Methods A narrative review was conducted (approval ID: IR.AMS.REC.1401.029), utilizing keyword searches in PubMed and Web of Science (WOS) citation index expanded (SCI‐EXPANDED) from January 2020 to January 2023. Keywords included COVID‐19, clinical research, barriers, obstacles, facilitators and enablers. Results Out of 2508 records retrieved, 43 studies were reviewed, providing valuable insights into the challenges and corresponding solutions for conducting clinical research during the COVID‐19 pandemic. The identified challenges were categorized into four main groups: issues related to researchers or investigators, issues related to participants and ethical concerns, administrative issues, and issues related to research implementation. To address these challenges, multiple strategies were proposed, including remote monitoring through phone or video visits, online data collection and interviews to minimize in‐person contact, development of virtual platforms for participant interaction and questionnaire completion, consideration of financial incentives, adherence to essential criteria such as inclusion and exclusion parameters, participant compensation, and risk assessment for vulnerable patients. Conclusion The COVID‐19 pandemic has significantly impacted clinical research, requiring the adaptation and enhancement of existing research structures. Although remote methods and electronic equipment have limitations, they hold promise as effective solutions during this challenging period.


| INTRODUCTION
The COVID-19 disease has caused millions of deaths around the world. The most common symptoms of the infection were respiratory problems, which caused the disease to spread rapidly. 1 At the beginning of the pandemic, measures such as quarantine, social distancing, rapid tracking of patients and restriction of presence in closed spaces, and crowding were carried out to control the disease. 2 In the absence of definitive treatment and effective vaccines, these measures were effective to some extent but negatively affected society. 3 The COVID-19 pandemic changed many aspects of human life worldwide, causing adverse social and economic consequences that will persist for years. 4,5 Research is a critical aspect of responding to public health emergencies. Research efforts from various groups were focused on the origin of the COVID-19 disease and management strategies, including drugs and vaccines through numerous clinical trials. 6 Health scientists were confronting COVID-19 and solving its complications with investigations, research, and clinical trials. Many researchers were faced with significant challenges due to the spread of COVID- 19. These issues include the unwillingness of volunteers and research participants, reductions in research funds due to shifting toward the treatment and hospitalization of the affected, and emerging difficulties in traveling and field investigations. Furthermore, stress and concerns about COVID-19 were shared among the participants, volunteers, research team, and scientists. 7 Field investigations are necessary for many studies, requiring the presence of scientists in the clinical environment. Furthermore, the presence of participants and volunteers is essential for many researchers. Ethical problems such as obtaining consent to participate in the research, explaining the purpose of the study, follow-ups, and referring vulnerable patients during the study were negatively affected by the pandemic. 8 Due to the rapid spread of the COVID-19 disease and its high mortality, there was an urgent need for research on medications, vaccines, improving diagnostic tools, and medical management, which was a challenge for scientists. 9,10 The COVID-19 pandemic has significantly impacted various clinical research methods, particularly clinical trials, which are crucial in evaluating the safety and efficacy of new medical treatments.
Many aspects of clinical trials, including patient recruitment, obtaining informed consent, and implementing interventions, were traditionally conducted in person by the research team. However, due to the pandemic, these processes have been disrupted, and alternative methods have had to be developed to ensure the continuity of clinical research while prioritizing the safety of participants and researchers. 11 The COVID-19 pandemic also affected clinical research about infectious diseases as well as other medical fields, including cancer, chronic diseases, obstetrics, and gynecology. 12,13 The COVID-19 pandemic led to the discontinuation of several significant health studies. This was primarily due to a lack of effective preparation for such a crisis and inadequate guidance for clinical researchers on addressing research challenges by utilizing various strategies rather than halting research in clinical settings.
As a result, many researchers were not equipped to adapt to the new circumstances and continue their studies safely and effectively.
However, it is crucial to note that innovative solutions have emerged in response to these challenges, such as remote data collection and telemedicine, which have enabled researchers to continue their work while ensuring the safety of study participants and staff. Going forward, it is essential to prioritize preparedness for potential crises and provide clear guidance to researchers to ensure the continuity of critical health studies during challenging times.
Previous reviews have examined the challenges of conducting research during the COVID-19 pandemic. However, these reviews are limited to clinical trials, research sponsors, or particular diseases. 7,14 A comprehensive review that examines all aspects of conducting clinical research during the pandemic is currently lacking, yet it is crucial for future crises. Therefore, we aimed to comprehensively review the challenges faced worldwide in conducting clinical research during the COVID-19 pandemic. We will also identify solutions to these challenges to aid researchers and policymakers in facilitating clinical research during future crises. By conducting this review, we hope to provide a comprehensive understanding of the impact of the pandemic on clinical research and contribute to the development of strategies to mitigate its effects on research activities.

| Search strategy and information sources
We searched PubMed and Web of Science (WOS) citation index expanded (SCI-EXPANDED) on January 4, 2023, to identify related articles published between January 2020 to January 2023. We developed the search strategy for the PubMed database and modified it for the WOS database ( Table 1). The search strategy was applied without any limitation on data and languages. Manual searching in key journals for relevant articles was conducted after the initial search of databases, and the reference list of included articles was checked for possible related studies ( Figure S1).

| Study selection process
Two authors reviewed and screened all retrieved documents independently (MN, MH) based on titles and abstracts according to the eligibility criteria. Afterward, the full texts of the selected studies were assessed. Any disagreements were resolved by the third author (NM).
The inclusion criteria consisted of studies conducted during the COVID-19 pandemic examining challenges related to conducting research regardless of their study design. There is no limitation on the type of studies. Articles without abstract, full-text, or sufficient relevant data were excluded.

| Data extraction
The list of data extraction included the first author's name, publication year, study design, and study country or setting. Information about the challenges and related solutions was extracted and reviewed from the included articles narratively. To categorize challenges, we used expert opinion.

| RESULTS
A total of 2508 records were retrieved through electronic databases.
After removing duplicates and screening based on title and abstract, the full texts of 156 studies were assessed, and 43 studies were included in the qualitative synthesis ( Figure S1).
All the studies were conducted during the COVID-19 pandemic and evaluated the challenges of conducting research in this era. The characteristics of the included studies are provided in Table 2.
The challenges included "issues related to researchers or investigators, issues related to participants and ethical concerns, administrative issues (i.e., research ethics committee [REC] or institutional review board [IRB] approval), and issues related to research conduction," which are reviewed in the following sections.

| Issues related to researchers or investigators
The increasing pressure of the pandemic on healthcare systems caused an extensive change in the employee workflow, increasing the duties of research personnel. 53 Research nurses had to work as clinical nurses in labor, delivery, and postpartum units. The pressure of researching clinical staff was significantly reduced, allowing them to respond to the patient's needs. 39 The research staffs were concerned about the risk of COVID-19. Exposure to the disease during face-to-face meetings increased the chance of infection.
Reducing the number of in-person meetings and planning them through video conferences were necessary to reduce the risk of disease transmission. Also, appropriate personal protective equipments were mandatory to address these concerns. 7,12 Although the COVID-19 limited medical students' classes and their presence in the hospital, many remained at their workplaces and engaged in their clinical and scientific activities. 54 At some institutions, medical students and residents played a more prominent role in screening, consenting, and enrolling clinical research participants. Tasks that were generally performed by research personnel. For example, residents performed research activities for high-priority research regarding public health concerns such as COVID-19 instead of research staff. 9 The participation of medical students in research varied in different countries and was related to the policies of each country and university. 55 The activity of medical students may be necessary and temporary in some critical times, such as the COVID- follow-up before and after interventions must be prioritized to continue trials. Confidentiality of patient data and the secure delivery of investigational treatments from trial sites are essential. Participants must also be provided with instructions for properly storing and using investigational drugs. 16,29 Result by Shields et al. 30 showed that fear of COVID-19 was a major barrier to follow-ups. This fear included patients who felt unsafe exposing themselves or their family members or a patient's family member feeling unsafe exposing the patient. The next most commonly reported barriers were long waiting times and financial costs.
Informed consent is a common and fundamental part of any clinical research. It is usually provided by paper forms that explain the purpose of the study, the procedures, and possible adverse effects and are signed by the participants. 28 Addicts, sex workers, and the homeless did not follow many health protocols. Many lived in the same room with several people and did not practice social distancing. These cases could cause the spread of the coronavirus to the researchers and others, endangering the health of the participants and study operators. 18,58 Another effective way to attract participants is through financial incentives. Allocating the necessary funding for these incentives is a task that health organizations should notice.
Providing essential funding, creating financial incentives, and paying attention to the participants' health can facilitate active participation in the research. 58 A study by Basel showed that statistically significant increases were seen in participants' consent rates and responses when offered even small monetary value incentives. These findings suggest that incentives may be used to reduce the rate of recruitment failure and subsequent study termination 60 (Table 3).
T A B L E 3 Challenges and solutions in clinical research during the COVID-19 pandemic.

Issues related to researchers or investigators
• Risk of transmission (among research staff and investigators Reference) 61 • Increasing workload of clinical nurses 7,9,39 • Using remote monitoring in the form of telephone and/or video visits 61 • Reduction the number of face-to-face meetings and planning for video conference • Using the patient's local facilities 61 • Assigning most of the research tasks to the research staff, medical students and residents 9,40 Issues related to participants and ethical concerns • Expansion and diversity in communication networks 6,19 • Using online methods to collect information and interview 19,37 • Changing the type of execution 19 • Creating online classes, online exercises, using videos and virtual networks 11,56 • Creating online platforms for responding to participants, and completing questionnaires 49 • Accessing to epidemiological data for collecting data 25,43 • Artificial intelligence and deep learning algorithm in analysis 21,25 • Adapting statistical methods to the pandemic conditions 64 • Reduction the number of face-to-face visits 7,15,51 • Visits are conducted remotely or via phone or video call 7,14 • Mailing drug to the participants 47 and sending the medicine directly to the patient's home by site personnel or sponsors 20,63 • Using volunteer registry for enrolment of patients 18 • Making strong communication and commitment to participants 52 • Creatingtechnologicalcapabilitiesforteleworking, 34 visits 35,47 • Motivating to perform procedures at the patient's home 63 • Permitting-use, healthcare facilities, 65 3.3 | Administrative issues (REC or IRB approval)

| Rapid review of research
Thousands of clinical trials were registered in the first few months of the pandemic, facing ethics committees with a high load of studies. A thorough review was necessary to prevent high-risk and low-benefit treatments on patients. IRBs had to prioritize specific issues such as inclusion or exclusion criteria, participant compensation, and risk assessments for vulnerable patients to facilitate rapid research review and management of time (Table 3).

| Ethical issues after IRBs
Despite ethical review board approval, many studies deviated from their protocols due to circumstances during the study. To ensure transparency and efficiency, modifications to pre-study documents, consent forms, study entry reports, conflict of interest, sponsorship, and side effects had to be reported to the ethics committee. This allowed for transparency and ensures that changes are made appropriately. 15,39

| Structure and process of IRB
Ethics committees faced the challenge of requiring a multidisciplinary team of experts in virology, infectious diseases, pharmaceuticals, and public health for quick and accurate document review. 28 To address this, committees should prioritize investigator-initiated trials from a public health perspective and expedite the review of academic trials that address important questions. Regulatory approval processes should be streamlined, redundancies in research design approval processes eliminated, and urgent public health trials facilitated. Experts in different fields can review these indicators. 39 To expedite the approval of interventional studies, having only one national ethics committee review and approve studies is recommended. This approval should be accepted throughout the country without needing re-approval by another hospital or city's ethics committee 20 (Table 3). The pandemic significantly impacted clinical trials, particularly in cases where patient follow-ups and randomization were halted, leading to economic losses. Many unnecessary experiments were stopped to prioritize the research with a greater benefit-to-harm ratio. 21 Ethically speaking, exposing trial participants to risk is unacceptable if the study is not designed to provide valid results.

| Clinical trials
Therefore, rigorous methodology should be implemented, including randomization, blinding, and placebo use, to enhance scientific validity and societal value. However, in severe epidemics, insisting on randomization can create a conflict between individual health and societal interests, precluding patients' autonomy in choosing their therapy. 66 20,36,45,63 Online platforms and social media were among the most practical strategies to reduce the imposed limitations. 29 Simmons et al. 46 replaced all in-person parts of their clinical study using two key technology platforms: Study Pages (Yuzu Labs Public Benefit Corporation, 2022) and Pattern Health (Durham, NC). Recruitment and screening, consent, enrollment, randomization, data collection, blinding, adherence, and retention were performed with these platforms.
While recruiting study subjects can be difficult in typical circumstances, the COVID-19 pandemic posed additional obstacles for individuals and children seeking to participate in pediatric nursing research. Skeens' study found that using social media to recruit a sample of parent-child dyads during the COVID-19 pandemic was an innovative technique. 51 In addition, an original web-based survey determined that social media was a successful and efficient technique for gathering data on COVID-19 in a short period of time. 27

Faster research dissemination
In response to COVID-19, the research community has rapidly adopted a new way of disseminating research. However, unfortunately, the way in which research is being conducted has not changed. There has been an unprecedented surge of COVID-19-related preprints and peer-reviewed publications. While preprint servers and faster peer review processes have clear merits, such as quicker dissemination of results, informing policies, and speeding up the R&D process for COVID-19 therapeutics and vaccines, the quality of COVID-19 research has been largely subpar.
Many preprints, which are not peer-reviewed, were rushed to dissemination without sufficient oversight, leading to potential inaccuracies and false claims. 31

Employing virtual platforms
Limited face-to-face interactions during the pandemic significantly reduced the number of research visits, and study evaluations, requiring most research visits to be conducted remotely or via phone or video calls. For example, in drug effectiveness studies, by editing the protocols, the study medications could be mailed to the participants instead of in-person deliveries. 7,15 The lack of experience regarding virtual platforms to implement clinical studies also affected the results. Lack of face-to-face communication, the reduction of interpersonal interaction between the researcher and the participants, and the accuracy of the acquired information were among the limitations that could cause bias in clinical studies. 39 Each remote data collection method has its advantages and disadvantages that determine its feasibility and acceptability in certain settings. For example, when considering a mobile phone survey, IVR and SMS surveys are more affordable than CATI, but require participants to have high literacy levels. CATI, on the other hand, allows for the inclusion of individuals regardless of their literacy level and provides opportunities for researchers to encourage participation and clarify questions. In low-and middle-income countries, where mobile phone ownership is widespread but access to smartphones and the internet is limited, mobile phone methods are more commonly used and are the focus of this commentary.
However, few experts interviewed had implemented or planned online strategies due to their limited reach in certain low-and middleincome countries. Some exceptions include online surveys designed for specific target groups, such as members of established professional associations and university students. Therefore, sample size calculations should be conducted before data collection begins, and researchers should devise a recruitment strategy that allows them to reach the previously defined sample. 32

| Data analysis
One of the essential component of clinical studies is statistical models methods. 22  There was also a need for an international committee of statistical experts to decide on statistical methods during the COVID-19 pandemic. 33,71 Additional measures were needed besides the usual strategies for conducting a clinical trial to deal with the mentioned challenges in a pandemic. The conditions of participation, measures needed to prevent infection, and the possibility of withdrawing from the study should be available before making decisions for participants at increased risk of infection. 7,24 3.4.4 | Research protocols and guidelines during a pandemic During a pandemic, data security, patient satisfaction, and ethical statements, which are necessary in non-pandemic situations, can be considered bureaucratic obstacles. However, rapid access to clinical data during epidemic circumstances requires special handling of these matters, which should be discussed nationally. 23 Another statistical challenge during the COVID-19 pandemic was that many clinical studies were not implemented according to written protocols due to the inability to blind, obtain a high sample size, and randomize.
Therefore, statistical methods must be adapted to pandemic conditions. Data should be collected and analyzed in a standardized way, and statisticians are encouraged to develop appropriate analytical strategies for data collected from standardized protocols such as ISARIC and LEOSS. Rapid and valid information flow and reporting are crucial during a pandemic, and long-lasting reporting guidelines may do more harm than good. Specific reporting guidelines are needed for pandemic settings. 23 Another challenge was related to studies started before the pandemic that were affected by COVID-19. Challenges included discontinuation of medication, withdrawal of a significant number of participants, deaths due to COVID-19, and changes in study arms, which were not foreseen and affect study designs. Changing and updating the study protocol, continuing the investigation, and performing sensitivity analysis for missing data can be suitable solutions. 25

| Comaprison with previous studies
Remote data collection requires much effort from the study participants, who may need to use their own resources, such as a phone, internet access, and identifying a private space to participate in the study. On the other hand, remote methods may be preferable for study participants and eliminate the time and opportunity costs associated with travel to study sites. As with any research, the potential risks must be weighed against the benefits and the ethical imperative to continue the research to produce evidence useful for public health. 37 Original studies also showed that remote data collection was an effective way to deal with the restrictions created by COVID-19. Also, original studies determined that using technology like social media was an effective strategy for conducting research. 27,51 Key challenges in remote data collection encompass gathering diverse experiences in qualitative research, obtaining a representative sampling frame of the target population in quantitative research, and reaching out to more accessible populations. 63,72 While some of these challenges also exist in face-to-face research, the limited ability to personally recruit participants, whether at home, in a clinic, or any other locations, along with the reliance on mobile phones for recruitment, poses a specific challenge. This necessitates the exploration of alternative sampling methods for qualitative research, including purposive, snowball, and convenience sampling. Purposive sampling aims to ensure diversity by considering key factors that are theorized to influence the experience. Recruitment can be facilitated through community-based organizations, influential community leaders, neighborhood health committees, or established networks. Snowball sampling can be an effective approach for qualitative research; however, it is crucial to involve several initial participants who can then recruit others from within their own networks to achieve the desired diversity. 73,74 These sampling methods can also be used in quantitative research. Snowball sampling may be useful for online surveys shared via email or social media platforms, 75  consented to participate in various study components, which can also serve as a record for audit purposes. 37 The privacy and safety of participants are crucial considerations when conducting research. In face-to-face studies, it is the responsibility of the researcher to establish and ensure privacy, and data collection must be halted if privacy is compromised. However, the onus is placed on the study participant in remote research to maintain their privacy. Nonetheless, establishing privacy can be challenging when participants share living spaces and have limited access to private areas and time. This becomes particularly significant in studies that examine sensitive topics like gender-based violence, where compromised privacy can have harmful consequences. 76 To address this issue, it is essential to inform participants about the potentially sensitive nature of the study at the beginning of data collection and encourage them to seek a private space. Strategies such as incorporating "passwords" or "exit buttons" can be implemented to mitigate risks. These mechanisms allow participants to verbally state or click on an option to indicate a breach of privacy. 76 IVR and online surveys allow participants to complete surveys at a time and place of their choice, enabling them to establish privacy more effectively. Furthermore, these surveys can include a question asking respondents whether they completed the survey in private or in the presence of someone else, such as their child, parent/guardian, or friend. 37 Data protection, including end-to-end encryption of phone calls and the security of platforms used to deliver online surveys and interview transcripts, is an additional privacy and confidentiality issue that needs to be addressed. 77 In addition, researchers have the duty of care and should carefully consider safeguarding issues, particularly where COVID-19 has affected the availability of support services.
Information about online or telephone services must be available during the consent process. Specific referral protocols should be established, interviewers should be notified if certain responses may trigger automatic referrals, and follow-up should be provided if safeguarding issues arise. As part of this protocol, researchers must establish a system to regularly check that these services remain operational. 42

| Strengths and limitations
This is the first review to study both the challenges and solutions of conducting clinical research during the COVID-19 pandemic, providing a practical guide for researchers and policymakers in future similar pandemic conditions. However, this study had some limitations. We had to rely on primary studies, as there was not enough information about the challenges of conducting studies in all types of research.
Additionally, the majority of the studies discussed in this article were in the form of editorials, highlighting the need for more rigorous studies to investigate the subject matter further.
Nevertheless, this study has proposed effective solutions that policymakers can consider for implementation in the context of decision-making for addressing the ongoing pandemic and future crises. Although WHO has declared the end of the COVID-19 pandemic, 65 this review can still provide valuable information to achieve structured guidelines for researchers in future crises.

| CONCLUSION
The study findings revealed significant challenges associated with conducting research during the COVID-19 era. These challenges span various stages, ranging from research inception and study approval to patient enrollment and data analysis. Existing solutions must be adapted to the prevailing circumstances, highlighting the importance of enhancing the underlying research infrastructure to ensure continuity during times of crisis and pandemics. Numerous studies have proposed remote methods and electronic equipment as viable approaches to conduct research. However, the successful implementation of these methods relies on the availability of adequate infrastructure and adherence to country-specific national and university policies.

ACKNOWLEDGMENTS
We would like to thank the Iranian Academy of Medical Sciences for approving the study protocol and for the financial support, which make this review possible. This study was supported financially by the Iranian Academy of Medical Sciences (IAMS).

CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.

DATA AVAILABILITY STATEMENT
All data associated with the article is available upon request.

ETHICAL STATEMENT
All the authors declare that the present work has been carried out per the Journal's Practice Guidelines on Publishing Ethics and has been performed ethically and responsibly, with no research misconduct.
The article has not been previously published and is not currently

TRANSPARENCY STATEMENT
The lead author Bagher Larijani affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.